CN108187073A - 一种载纳米颗粒的药物组合物、制备方法及其应用 - Google Patents
一种载纳米颗粒的药物组合物、制备方法及其应用 Download PDFInfo
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Abstract
本发明公开了一种载纳米颗粒的药物组合物,包含如下重量份数的组分:纳米颗粒1~10份;发泡剂20~50份;粘附性材料5~30份;填充剂1~80份;矫味剂0~10份;还包括1~40重量份的目标药物。本发明还公开了药物组合物在制备治疗消化道炎症药物、抗肿瘤药物或医学影像造影剂中的应用。不同于目前常用的静脉注射式造影剂和治疗药物,本发明是将含纳米颗粒的药物组合物混合压片制成口服粘附片,经口服粘附在胃壁上,接触胃酸后胃酸与发泡剂发生反应稳定持续性产生载药气泡,进行缓慢药物释放,可由超声等方式将载药气泡所携带的纳米颗粒和治疗疾病的药物引导至病变部位,可用于检测或治疗。
Description
技术领域
本发明属于医药技术领域,涉及一种靶向治疗的药物组合物,具体涉及一种载纳米颗粒的药物组合物、制备方法及其应用。
背景技术
随着纳米药物和微纳气泡载药技术的日益发展,纳米颗粒与载药气泡的结合已成为临床治疗研究的热点。然而纳米颗粒及载药气泡的给药在当前的主流研究中都是以静脉注射的方式。经研究调查得知,如果可以进行自主选择,患者普遍倾向于口服给药胜过静脉注射给药。
口服给药是将药物直接通过消化器官进入体内的一种给药方式,由于这种给药方式能够直接进入到胃肠道中,能够作为针对胃肠道的局部给药方式,也能通过胃肠消化器官的吸收作用进入到血管中,参与血液的循环达到全身性给药的作用。胃肠道的器官因其巨大的表面积,有助于增加药物的吸收,是当前口服给药研究中的一个特别有吸引力的目标位点。值得注意的是,由于消化道上皮细胞的快速扩散和流动,给重复定量给药带来可能,并且可以达到细胞毒性的最小化。不过,口服给药最主要的挑战,目前在于作为消化器官的胃肠结构存在大量的消化酶以及其细胞存在吸收壁障,造成药物吸收过程产生的首过效应。因此,纳米药物的口服给药方式,逐渐成为当今药物递送的研究热点。
用气泡作为靶向药物运输载体的方法目前已经得到发展,如超声微气泡等,可以携带检测药物靶向运输到病变组织部位,达到靶向检测、靶向治疗的目的。但目前的气泡制备方法,仍多是使用体外起泡,静脉注射的方式,对操作有一定技术要求。
同时,随着医学、计算机以及生物工程技术方面的发展,多模态医学影像方法逐渐广泛应用于临床中肿瘤、心血管方面诊断研究。多模态医学影像技术尝试融合了CT、PET、MRI等多种模态影像学优势,力图最大限度地挖掘影像学信息,将不同模态图像信息融合在一起,反映出更丰富的病变组织和器官的综合信息,充分显示组织形态,体现分辨力高、定位准确的优势,从而作出更准确的诊断和治疗。然而,目前应用于多模态医学影像方法的造影剂,大多是采用静脉注射的方式,操作有一定技术要求,也有一定的风险,不利于多模态医学影像的广泛推广。
发明内容
发明目的:为了解决现有技术中纳米药物静脉注射存在的问题,本发明提供了一种可口服的载纳米颗粒的药物组合物,基于多模态医学影像以及超声诊疗一体化,可用于制备治疗消化道炎症、肿瘤药物或医学影像造影剂等。
技术方案:本发明所述一种载纳米颗粒的药物组合物,包含如下重量份数的组分:纳米颗粒1~10份;发泡剂20~50份;粘附性材料5~30份;填充剂1~80份;矫味剂0~10份。
优选地,所述药物组合物还包括1~40重量份的目标药物。
更优选地,所述药物组合物包括如下重量分数的组分:根据配方具体作用可进行调整,纳米颗粒0.5~1.5份;目标药物20~30份;发泡剂1~35份;粘附性材料10~20份;填充剂20~50份;矫味剂0~5份。
所述目标药物为用于治疗消化道炎症的药物、抗肿瘤药物和医学影像造影剂中的任意一种或几种。
所述用于治疗消化道炎症的药物为阿莫西林、奥美拉唑和兰索拉唑中的任意一种或几种。所述抗肿瘤药物为氟尿嘧啶类药物、顺铂、紫杉烷类药物和表柔比星中的任意一种或几种;所述氟尿嘧啶类药物为卡培他滨和替吉奥中的任意一种或几种;所述紫衫烷类药物为紫杉醇和多西他赛中的任意一种或几种。
所述医学影像造影剂为硫酸钡、碘制剂、钆喷酸葡胺和钆特酸葡胺中的任意一种或几种;所述碘制剂为无机碘化物(一般为1~12.5wt.%碘化钠水溶液)、有机碘化物(泛影葡胺、碘普洛胺)、碘化油或脂肪酸碘化物(如碘苯酯)中的任意一种或几种。
所述纳米颗粒为超顺磁性氧化铁纳米颗粒、四氧化三铁纳米颗粒、普鲁士蓝纳米颗粒、纳米金颗粒、纳米银颗粒和碲化镉量子点中的任意一种或几种。所述纳米颗粒的作用为:超顺磁性纳米氧化铁颗粒和四氧化三铁纳米颗粒对MRI造影的增强作用、普鲁士蓝纳米颗粒的类酶效应、纳米金颗粒和纳米银颗粒对影像学成像的增敏作用、碲化镉量子点的荧光成像增强效果。所述发泡剂为碳酸氢钠、碳酸钠和碳酸镁中的任意一种或几种;所述粘附性材料为卡波姆934P、黄原酸和HPMC(羟丙基甲基纤维素)中的任意一种或几种,所述填充剂为滑石粉、玉米淀粉、甘露醇、乳糖中的任意一种或几种,所述矫味剂为柠檬酸、蔗糖、单糖浆、芳香糖浆和山梨醇中的任意一种或几种。所述HPMC优选为HPMC K4M。优选地,药物组合物的剂型为片剂。
本发明进一步的目的是提供上述药物组合物的制备方法,包括以下步骤:
(1)将配方量的纳米颗粒、目标药物、发泡剂、填充剂、矫味剂和粘附性材料混合均匀,过筛;
(2)湿法或干法制粒压片。其中,所述过筛是指80目筛。所述压片包括步骤(1)得到的混合物直接称量压片或在步骤(1)得到的混合物中根据总固体重量每3~6g滴加0.5~1.5mL粘合剂或湿润剂,湿法制粒干燥后,再称量压片。
所述粘合剂为淀粉浆(淀粉与水混合,水质量为淀粉质量1~1.5倍)、糊精水溶液(糊精与水混合,水质量是糊精质量2~3倍)和羟甲基纤维素水溶液(羟甲基纤维素的质量分数大于等于5%)中的任意一种或几种;所述湿润剂为水、无水乙醇,湿润剂还可以是和纳米颗粒水溶液所述纳米颗粒水溶液为超顺磁性氧化铁纳米复水溶液(1~10mg/mL)、纳米金水溶液(0.5~5mg/mL)、纳米银水溶液(1~10mg/mL)、普鲁士蓝纳米颗粒水溶液(0.5~10mg/mL);采用湿法制片时,当湿润剂为纳米颗粒水溶液时,优选地,步骤(1)中将配方量的目标药物、发泡剂、填充剂、矫味剂和粘附性材料混合均匀,过筛;步骤(2)中湿法制粒压片时,再将配方量的纳米颗粒溶于水中制成纳米颗粒水溶液,既作为湿润剂,同时作为组合物的有效成分。
本发明更进一步的目的是提供上述药物组合物在制备治疗消化道炎症药物、抗肿瘤药物或医学影像造影剂中的应用。
有益效果:与现有技术相比,本发明的优势如下:
不同于目前常用的静脉注射式造影剂和治疗药物,本发明是将含纳米颗粒的药物组合物混合压片制成口服粘附片,经口服粘附在胃壁上,接触胃酸后胃酸与发泡剂发生反应稳定持续性产生携带纳米颗粒和功能性药物的载药气泡,进行缓慢药物释放,并由超声等方式将载药气泡所携带的纳米颗粒和治疗疾病的药物引导至病变部位,可用于检测或治疗。通过调整粘附性材料的剂量,可使纳米颗粒和治疗疾病的药物快速释放,并能保证有效成分不被胃酸过快侵蚀。该组合物作用温和、操作简便、使用安全,且制备得到的片剂符合药学粘附片标准。
附图说明
图1为治疗流程图;
图2为药物组合物在体内释放的流程图。
具体实施方式
一种载纳米颗粒的药物组合物,包含如下重量份数的组分:纳米颗粒1~10份;发泡剂20~50份;粘附性材料5~30份;填充剂1~80份;矫味剂0~10份。
优选地,所述药物组合物还包括1~40重量份的目标药物。
更优选地,所述药物组合物包括如下重量分数的组分:根据配方具体作用可进行调整,纳米颗粒0.5~1.5份;目标药物20~30份;发泡剂1~35份;粘附性材料10~20份;填充剂20~50份;矫味剂0~5份。
所述目标药物为用于治疗消化道炎症的药物、抗肿瘤药物和医学影像造影剂中的任意一种或几种。
所述用于治疗消化道炎症的药物为阿莫西林、奥美拉唑和兰索拉唑中的任意一种或几种。所述抗肿瘤药物为氟尿嘧啶类药物、顺铂、紫杉烷类药物和表柔比星中的任意一种或几种;所述氟尿嘧啶类药物为卡培他滨和替吉奥中的任意一种或几种;所述紫衫烷类药物为紫杉醇和多西他赛中的任意一种或几种。
所述医学影像造影剂为硫酸钡、碘制剂、钆喷酸葡胺和钆特酸葡胺中的任意一种或几种;所述碘制剂为无机碘化物(一般为1~12.5wt.%碘化钠水溶液)、有机碘化物(泛影葡胺、碘普洛胺)、碘化油或脂肪酸碘化物(如碘苯酯)中的任意一种或几种。
所述纳米颗粒为超顺磁性氧化铁纳米颗粒、四氧化三铁纳米颗粒、普鲁士蓝纳米颗粒、纳米金颗粒、纳米银颗粒和碲化镉量子点中的任意一种或几种。所述发泡剂为碳酸氢钠、碳酸钠和碳酸镁中的任意一种或几种;所述粘附性材料为卡波姆934P、黄原酸和HPMC(羟丙基甲基纤维素)中的任意一种或几种,所述填充剂为滑石粉、玉米淀粉、甘露醇、乳糖中的任意一种或几种,所述矫味剂为柠檬酸、蔗糖、单糖浆、芳香糖浆和山梨醇中的任意一种或几种。所述HPMC优选为HPMC K4M。优选地,药物组合物的剂型为片剂。
本发明进一步的目的是提供上述药物组合物的制备方法,包括以下步骤:
(1)将配方量的纳米颗粒、目标药物、发泡剂、填充剂、矫味剂和粘附性材料混合均匀,过筛;
(2)湿法或干法制粒压片。其中,所述过筛是指80目筛。所述压片包括步骤(1)得到的混合物直接称量压片或在步骤(1)得到的混合物中根据总固体重量每3~6g滴加0.5~1.5mL粘合剂或湿润剂,湿法制粒干燥后,再称量压片。
所述粘合剂为淀粉浆(淀粉与水混合,水质量为淀粉质量1~1.5倍)、糊精水溶液(糊精与水混合,水质量是糊精质量2~3倍)和羟甲基纤维素水溶液(羟甲基纤维素的质量分数大于等于5%)中的任意一种或几种;所述湿润剂为水、无水乙醇,湿润剂还可以是和纳米颗粒水溶液所述纳米颗粒水溶液为超顺磁性氧化铁纳米复水溶液(1~10mg/mL)、纳米金水溶液(0.5~5mg/mL)、纳米银水溶液(1~10mg/mL)、普鲁士蓝纳米颗粒水溶液(0.5~10mg/mL);采用湿法制片时,当湿润剂为纳米颗粒水溶液时,优选地,步骤(1)中将配方量的目标药物、发泡剂、填充剂、矫味剂和粘附性材料混合均匀,过筛;步骤(2)中湿法制粒压片时,再将配方量的纳米颗粒溶于水中制成纳米颗粒水溶液,既作为湿润剂,同时作为组合物的有效成分。
实施例1制备载纳米金颗粒的口服粘附片
将碳酸氢钠1.5g、玉米淀粉2.1g、卡波姆0.75g、HPMC 0.75g、甘露醇0.9g混合过80目筛,然后将混合粉末进行湿法制粒压片,即向混合粉末中加入纳米金水溶液(1mL,1mg/mL作为润湿剂和有效成分),过16目筛进行造粒,微干燥后,过12目筛整粒,进一步干燥后进行称量压片,得到20片(片重分别为每片300mg)载纳米金颗粒口服粘附片,片剂符合药学粘附片标准。
实施例2制备载纳米银颗粒的口服粘附片
制备方法同实施例1,不同的是向混合粉末中加入纳米银水溶液(1mL,1mg/mL作为润湿剂和有效成分)。得到20片(片重每片300mg)载纳米银颗粒、有辐射增敏效果的口服粘附片,片剂符合药学粘附片标准。
实施例3制备载超顺磁性氧化铁颗粒的口服粘附片
制备方法同实施例1,不同的是向混合粉末中加入超顺磁性纳米氧化铁水溶液(1mL,5.73mg/mL作为润湿剂。得到20片(片重每片300mg)载超顺磁性纳米氧化铁颗粒的口服粘附片,片剂符合药学粘附片标准。
实施例4奥美拉唑口服粘附片及其药理药代效果
将碳酸氢钠1.5g、玉米淀粉2.1g、卡波姆0.75g、HPMC 0.75g、奥美拉唑0.4g、甘露醇0.5g混合过筛,然后加入1mL5.73mg/mL的超顺磁性纳米氧化铁复溶液,微干燥后湿法压片,得到20片(片重300mg)奥美拉唑口服粘附片,片剂符合药学粘附片标准。片剂接触胃酸产生粘附力粘附于胃壁,进行药物缓释,碳酸氢钠与胃酸反应释放自由气泡,促进片剂溶解释放,结合体内超声作用,引导气泡进行惯性空化作用,促进奥美拉唑释放和吸收,见图1和图2。
奥美拉唑为质子泵抑制剂,容易浓集于酸性环境中,抑制胃酸分泌。体外释放按照药典方法配置模拟胃酸溶液:取药典规定浓度稀盐酸水溶液(9.5~10.5wt.%)16.4mL,加水800mL,摇匀后,加水稀释定容成1000mL。取药片置于25mL圆底烧瓶中,加入15mL模拟胃酸进行溶出,在每个时间点取1mL溶出液,并补液(模拟胃酸)1mL。体外结果表明,在超声作用下,奥美拉唑口服粘附片在0.5h内释放率达85.3%。与没有超声作用下的释放(18.3%)相比,释放速率提高4.66倍。超声作用条件下,奥美拉唑口服粘附片完全释放需要1.5h,没有超声作用,奥美拉唑口服粘附片完全释放需要3.75h。
奥美拉唑在体内以代谢方式进行消除,血浆消除半衰期为0.5~1h,血药浓度给药后4~6h基本消失,其中72%~80%经肾脏排出,18%~23%经胆汁分泌随粪便排出。
实施例5卡培他滨口服粘附片及其药理药代效果
将碳酸氢钠1.5g、玉米淀粉2.1g、卡波姆0.75g、HPMC 0.75g、卡培他滨0.9g混合过筛,1mL5.73mg/mL的超顺磁性纳米氧化铁复溶液,微干燥后湿法压片,得到20片(片重300mg)卡培他滨口服粘附片,片剂符合药学粘附片标准。片剂接触胃酸,片剂产生粘附力粘附与胃壁,进行药物缓释,碳酸氢钠与胃酸反应释放自由气泡,促进片剂溶解释放,结合体内超声作用,引导气泡进行惯性空化作用,促进卡培他滨释放和吸收。
体外释放按照药典方法配置模拟胃酸溶液:取药典规定浓度稀盐酸(9.5~10.5wt.%)16.4mL,加水800mL,摇匀后,加水稀释定容成1000mL。取药片置于25mL圆底烧瓶中,加入15mL模拟胃酸进行溶出,在每个时间点取1mL溶出液,并补液(模拟胃酸)1mL。体外结果表明,在超声作用下,卡培他滨口服粘附片在0.5h内释放率达87.5%。与没有超声作用下的释放(15.1%)相比,释放速率提高5.79倍。超声作用条件下,卡培他滨口服粘附片完全释放需要1.5h,没有超声作用,卡培他滨口服粘附片完全释放需要3.75h。
卡培他滨是氟尿嘧啶类口服抗肿瘤药物,经过胃肠道完全吸收,经肝脏羧酸酯酶催化代谢为5’-脱氧-5-氟胞苷(5’-DFCR),然后经肝脏和肿瘤细胞中的胞苷脱氨酶催化转化为5’-脱氧-氟尿嘧啶(5’-DFUR),最后经胸苷磷酸化酶(TP)催化转化为FU发挥细胞毒作用(3步激活机制)。用药2h后5’-DFCR,5’-DFUR和5-FU的血药浓度达到峰值。用药3-4h后,FU的分解产物α-氟-β-丙氨酸(FBAL)达到峰值,其消除时间约为2.6-11.5h。卡培他滨的代谢产物(主要为FBAL)约71%由肾脏排出。
实施例6制备载超顺磁性纳米氧化铁颗粒的快速释放口服片
将碳酸氢钠1.4g、乳糖/甘露醇(重量比10:1混合物)2.2g、HPMC K4M 0.4g混合过筛,加入1mL5.73mg/mL的超顺磁性纳米氧化铁复溶液,微干燥后湿法压片,进一步干燥,得到20片(片重200mg)载超顺磁性纳米氧化铁颗粒快速释放口服片,片剂符合药学粘附片标准。
实施例7硫酸钡(I)型X射线造影快速释放口服片及其药理药代效果
将碳酸氢钠1.4g、乳糖/甘露醇(重量比10:1混合物)1.2g、HPMC K4M 0.4g、硫酸钡(I)型粉末1g分别混合过筛,加入1mL5.73mg/mL的超顺磁性纳米氧化铁复溶液,微干燥后湿法压片,得到20片(片重200mg)硫酸钡(I)型X射线造影快速释放口服片,片剂符合药学粘附片标准。
按照药典配置模拟胃酸溶液:取药典规定浓度稀盐酸(9.5~10.5wt.%)16.4mL,加水800mL,摇匀后,加水稀释定容成1000mL。取药片置于25mL圆底烧瓶中,加入15mL模拟胃酸进行溶出。结果表明,在超声作用下,硫酸钡(I)从粘附片中在0.5h内释放率达83.8%。超声作用条件下,硫酸钡(I)口服粘附片完全释放需要1.25h,没有超声作用,硫酸钡(I)口服粘附片完全释放需要3.5h。口服片在释放过程中,由于释放的碳酸氢钠与胃酸反应释放自由气泡,可用于增强超声内镜显影效果,进而,释放的硫酸钡(I)型可增强X射线造影,超顺磁性纳米氧化铁颗粒可增强MRI造影效果,实现MRI-超声-X射线多模态增强造影。
硫酸钡(I)型口服后不被胃肠道吸收,以原形从粪便排出。
Claims (10)
1.一种载纳米颗粒的药物组合物,其特征在于,包含如下重量份数的组分:纳米颗粒1~10份;发泡剂20~50份;粘附性材料5~30份;填充剂1~80份;矫味剂0~10份。
2.根据权利要求1所述的药物组合物,其特征在于,所述药物组合物还包括1~40重量份的目标药物。
3.根据权利要求2所述的药物组合物,其特征在于,所述目标药物为用于治疗消化道炎症的药物、抗肿瘤药物和医学影像造影剂中的任意一种或几种。
4.根据权利要求3所述的药物组合物,其特征在于,所述用于治疗消化道炎症的药物为阿莫西林、奥美拉唑和兰索拉唑中的任意一种或几种;所述抗肿瘤药物为氟尿嘧啶类药物、顺铂、紫杉烷类药物和表柔比星中的任意一种或几种。
5.根据权利要求3所述的药物组合物,其特征在于,所述医学影像造影剂为硫酸钡、碘制剂、钆喷酸葡胺和钆特酸葡胺中的任意一种或几种。
6.根据权利要求1或2任一所述的药物组合物,其特征在于,所述纳米颗粒为超顺磁性氧化铁纳米颗粒、四氧化三铁纳米颗粒、普鲁士蓝纳米颗粒、纳米金颗粒、纳米银颗粒和碲化镉量子点中的任意一种或几种。
7.根据权利要求1或2任一所述的药物组合物,其特征在于,所述发泡剂为碳酸氢钠、碳酸钠和碳酸镁中的任意一种或几种;所述粘附性材料为卡波姆934P、黄原酸和羟丙基甲基纤维素中的任意一种或几种,所述填充剂为滑石粉、玉米淀粉、甘露醇和乳糖中的任意一种或几种,所述矫味剂为柠檬酸、蔗糖、单糖浆、芳香糖浆和山梨醇中的任意一种或几种。
8.根据权利要求1或2任一所述的药物组合物,其特征在于,所述药物组合物的剂型为片剂。
9.权利要求8所述的药物组合物的制备方法,其特征在于,包括以下步骤:
(1)将配方量的纳米颗粒、目标药物、发泡剂、填充剂、矫味剂和粘附性材料混合均匀,过筛;
(2)湿法或干法制粒压片。
10.权利要求2所述的药物组合物在制备治疗消化道炎症药物、抗肿瘤药物或医学影像造影剂中的应用。
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